Cryptococcus neoformans, the most common cause of fatal fungal infections in patients with AIDS, is acquired via the respiratory tract. Host defense against C. neoformans is dependent upon communication between cells of the innate immune system and T cells. Transport of antigen from the site of initial exposure (lung) to T cell areas of the draining lung associated lymph nodes (LALN) precedes the induction of specific T cell immunity. Transport of antigen via the afferent lymphatics is a specialized function of dendritic cells. Highly controlled movement of monocytic DC precursors from the blood into sites of microbial infection and their subsequent activation/maturation and migration into LALN is crucial for induction of protective immune responses. The molecular signals that regulate the in vivo movement of monocytic DC precursors and DC between different compartments in the lung are poorly understood. Our preliminary studies document that a) CCR2 is crucial to the migration of CD11+ DC; and b) TNF-alpha and IFN-gamma are crucial links between the innate immune response and protective antigen-specific responses to C. neoformans. Hypothesis: CCR2 dependent recruitment of monocytes and/or monocyte-derived DC to the lung is required for generation of a protective T1 immune response to C. neoformans. These phagocytic, uncommitted, immature DC are uniquely capable of high level IL-12 p70 production if early pulmonary TNF-alpha and IFN-gamma drive their maturation. The specific aims are: Specific Aim 1: To determine the cells responsible for transport of antigen from the airspaces to LALN during the development of a specific, protective T cell response to pulmonary Cneo and determine the role of CCR2 in migration of these antigen presenting cells. Specific Aim 2: To determine the CCL responsible for CCR2-mediated antigen presenting cell migration during the development of a specific, protective response to pulmonary Cneo infection. Specific Aim 3: To determine the role of inflammatory mediators (IFN-gamma, TNF-alpha, PGE2) in regulating Cneo-induced IL-12 production by immature DC. Specific Aim 4: To determine the effect of transient lung (TNF-alpha) and IFN-gamma transgene expression on pulmonary antigen-presenting cell phenotype, lymphokine expression, pulmonary clearance, and brain dissemination in Cneo challenged CCR2 -/- mice. Specific Aim 5: To determine the effect of adoptive transfer of Cneo pulsed CCR2+/+BMDC into Cneo-infected CCR2 -/- mice.